In our earlier international patent applications Nos. WO 94/24263, WO 96/04947, WO 96/12513, WO 96/20022 and WO 96/25190, we disclosed various non-invasive drug delivery systems involving the use of a delivery device such as a needleless syringe or catheter which fires particles consisting of or containing a drug (which term includes genetic material) in controlled doses into body tissue, e.g. through the intact skin, for curative, prophylactic, diagnostic or other medical treatment.
The devices described in the earlier applications are constructed as a tubular nozzle or other lumen, a rupturable element initially closing the passage through the lumen adjacent to the upstream end of the lumen, drug particles located adjacent to the lumen, and energising means for applying to the upstream side of the element a gaseous pressure sufficient to burst the element and to produce within the lumen a supersonic condition and hence cause the particles to be fired from the downstream end of the lumen. In a first type of syringe, the supersonic condition is a supersonic flow of the gas through a nozzle, in which the drug particles are entrained. In that case the particles may be initially located within a rupturable capsule which provides the rupturable element. In the second type of syringe or catheter, the downstream end of the lumen is provided with a bistable diaphragm, which is movable between an inverted position in which it presents outwardly of the lumen a concavity containing the particles, and an everted, outwardly convex, position. The supersonic condition is then a supersonic shockwave which is arranged to snap the diaphragm over from its inverted to its everted position, and to catapult the particles outwardly.
The energising means: disclosed in the earlier applications has, in general, involved the use of a container for compressed gas, the container having an outlet provided with a valve which is opened manually by the operator. Various kinds of valves have been proposed, including a ball valve, in which the ball is pushed off its seat, a piston which is pushed out of sealing engagement with a cylindrical passageway, and a hollow needle which is advanced to pierce a foil closing the container outlet. However, all these solutions suffer from the possible disadvantage that upon manual operation to open the valve, the immediate and subsequent gas flow will depend upon the manipulation of the valve by the operator. In particular, if the valve is not fully opened quickly, the gas may not escape at the desirable maximum flow rate. In contrast, it is desirable that the escape of gas from the container should be substantially immediate, unimpeded, and reliably reproducible on every occasion, so that the characteristics of delivery of the dose of particles, and hence the depth of penetration into the patient., are accurately predetermined.
In accordance with the present invention, a needleless drug particle delivery device, of the kind in which firing of the drug particles is caused by a sudden gas flow, is characterised in that the device comprises a container of compressed gas and a mechanism for releasing the gas from the container to create the gas flow, the mechanism comprising a rupture element for breaching the container and a manually manipulable actuator for moving the element and the container relatively to one another to provide an initial breach whereby gas is released to act on a piston portion to provide a servo action which causes the rupture element and container to move further suddenly relatively to one another to complete the breaching of the container and establish a maximum gas flow from the container.
With this construction,. after the container has been breached manually, and the gas has been released into a volume, which will normally remain fixed while the gas pressure builds up to a value at which resistance to movement of the piston portion is overcome, the servo action will take over and cause full release of the gas in a predetermined manner, irrespective of any uncertain manipulation of the actuator.
The gas flow may be arranged to burst and then flow through a rupturable membrane to cause a shockwave to be transmitted along a lumen to an evertible diaphragm. Alternatively the gas flow may open a drug particle-containing capsule, by bursting a rupturable wall of the capsule or otherwise, to enable the gas flow to entrain particles contained in the capsule.
The rupture element may be a pusher for initially cracking, and subsequently substantially snapping off, a tip of the compressed gas container. Alternatively, the rupture element may be a piercing device, such as a hollow needle, for piercing a foil closing an outlet of the container, or a cutter or blade to cut or slice the outlet of the container.
The actuator may be a slidable or rotary finger or thumb piece provided with a ramp or other cam for providing the initial displacement of the rupture element upon movement of the actuator relatively to a body of the device. When the actuator moves linearly relatively to the rupture element, it may be moved by shortening the device telescopically, eg by pushing a part at the upstream end of the device with a part at the downstream end of the device in contact with the target until the container is breached. In either case the outlet of the container may point towards the upstream end of the device to minimise the possibility of any fragments, which are produced upon rupture of the container, being entrained by the gas and adulterating the particles. Equally, the container outlet may point downstream.
Although the piston portion could be formed on the gas container or by part of a cradle for the gas container, it is most simply provided for movement with, and normally integrated with, the rupture element. In one compact arrangement, the drug particles are arranged to be contained within a capsule, particularly a capsule with rupturable walls, which is mounted within a hollow piston, itself integrated with the rupture element. With this arrangement the rupture element and piston are moved a small distance by manual manipulation of the actuator to breach the container whereafter the gas pressure advances the piston and completes the breaching of the container, until the piston bottoms out. The full gas pressure is then applied to the capsule which is thus opened by rupture of its wall or otherwise, to release the full gas flow through the piston and capsule with the particles entrained in the flow.
In one arrangement of this invention the gas container is a cartridge fitted with a protruding nib-end that can be broken off to reveal an aperture through which the gas can escape. A primary manual leverage action has only to bend over the nib-end a short distance out-of-line in order to initiate a fracture crack and release gas at its junction with the cartridge. The consequent intensification of gas pressure behind the servo-piston propels the nib-end a farther distance out-of-line, progressively enlarging the aperture and, with an increased flowrate of gas, accelerating the movement until the nib-end shears off nearly or completely. This secondary servo action takes place automatically without any additional manual effort or travel, and the nib-end is held captive by the servo-piston element to prevent its interfering with or becoming entrained in the gas stream from the cartridge. This two-stage system of breaching the gas cartridge benefits from the rapidly increasing pressure force applied to the servo-piston, whereas other possible breaching mechanisms may have a constant level or suffer from a diminution of energy after making their initial impact movement.
The depth of dermal penetration of the drug particles is dependent upon the velocity at which the particles are delivered, and this in turn depends upon the velocity of the gas flow in which the particles are entrained, or the velocity of the shockwave when the particles are ejected from an evertible diaphragm. Different drugs need to be delivered to different depths in the tissue at which their activity is maximised. Skin of persons of different age has different penetrability. It is therefore desirable to be able to control accurately, and with reliable reproducibility, the velocity at which the drug particles are delivered, and for the velocity to be adjustable so that a single syringe can be used with different drugs and with persons of different age. We have appreciated that a simple way of being able to adjust the particle velocity is to set the maximum flow of gas from the container. This in turn can be achieved by adjusting the extent to which the container is breached, when the breaching has been completed, thereby utilising an adjustable restriction to the outflow of gas from the container. A simple way of providing such adjustment in the maximum gas flow is to provide an adjustable stop which limits the stroke of the piston portion at a set position. For example, when the container is a cartridge fitted with a protruding nib-end, progressive bending of the nib-end out-of-line, will progressively open the cartridge outlet and hence progressively increase the gas flow. Limiting the stroke of the piston portion, by appropriate setting of the stop, will then provide a predetermined gas flow from the cartridge.